Person: Leza Cerro, Juan Carlos
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First Name
Juan Carlos
Last Name
Leza Cerro
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Medicina
Department
Farmacología y Toxicología
Area
Farmacología
Identifiers
14 results
Search Results
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Item Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology(Journal of Neuroinflammation, 2021) Ben Afia, Amira; Vila, Èlia; Ormazabal, Aida; Haro, Josep M.; Artuch, Rafael; Ramos, Belén; Mac-Dowell Mata, Karina Soledad; Leza Cerro, Juan Carlos; García Bueno, BorjaBackground: The cortico-cerebellar-thalamic-cortical circuit has been implicated in the emergence of psychotic symptoms in schizophrenia (SZ). The kynurenine pathway (KP) has been linked to alterations in glutamatergic and monoaminergic neurotransmission and to SZ symptomatology through the production of the metabolites quinolinic acid (QA) and kynurenic acid (KYNA). Methods: This work describes alterations in KP in the post-mortem prefrontal cortex (PFC) and cerebellum (CB) of 15 chronic SZ patients and 14 control subjects in PFC and 13 control subjects in CB using immunoblot for protein levels and ELISA for interleukins and QA and KYNA determinations. Monoamine metabolites were analysed by high-performance liquid chromatography and SZ symptomatology was assessed by Positive and Negative Syndrome Scale (PANSS). The association of KP with inflammatory mediators, monoamine metabolism and SZ symptomatology was explored. Results: In the PFC, the presence of the anti-inflammatory cytokine IL-10 together with IDO2 and KATII enzymes decreased in SZ, while TDO and KMO enzyme expression increased. A network interaction analysis showed that in the PFC IL-10 was coupled to the QA branch of the kynurenine pathway (TDO-KMO-QA), whereas IL-10 associated with KMO in CB. KYNA in the CB inversely correlated with negative and general PANSS psychopathology. Although there were no changes in monoamine metabolite content in the PFC in SZ, a network interaction analysis showed associations between dopamine and methoxyhydroxyphenylglycol degradation metabolite. Direct correlations were found between general PANSS psychopathology and the serotonin degradation metabolite, 5-hydroxyindoleacetic acid. Interestingly, KYNA in the CB inversely correlated with 5-hydroxyindoleacetic acid in the PFC. Conclusions: Thus, this work found alterations in KP in two brain areas belonging to the cortico-cerebellar-thalamic-cortical circuit associated with SZ symptomatology, with a possible impact across areas in 5-HT degradation.Item Paliperidone reverts Toll-like receptor 3 signaling pathway activation and cognitive deficits in a maternal immune activation mouse model of schizophrenia(Neuropharmacology, 2017) Mac-Dowell Mata, Karina Soledad; Munarriz Cuezva, Eva; Caso Fernández, Javier Rubén; Muñoz Madrigal, José Luis; Zabala, Arantzazu; Meana, J. Javier; García Bueno, Borja; Leza Cerro, Juan CarlosThe pathophysiology of psychotic disorders is multifactorial, including alterations in the immune system caused by exogenous or endogenous factors. Epidemiological and experimental studies indicate that infections during the gestational period represent a risk factor to develop schizophrenia (SZ) along lifetime. Here, we tested the hypothesis that the antipsychotic paliperidone regulates immune-related brain effects in an experimental model of SZ. A well described prenatal immune activation model of SZ in mice by maternal injection of the viral mimetic poly(I:C) during pregnancy was used. Young-adult offspring animals (60PND) received paliperidone ip (0.05 mg/kg) for 21 consecutive days. One day after last injection, animals were submitted to a cognitive test and brain frontal cortex (FC) samples were obtained for biochemical determinations. The adults showed an activated innate immune receptor TLR-3 signaling pathway, oxidative/nitrosative stress and accumulation of pro-inflammatory mediators such as nuclear transcription factors (i.e., NFκB) and inducible enzymes (i.e., iNOS) in FC. Chronic paliperidone blocked this neuroinflammatory response possibly by the synergic activation and preservation of endogenous antioxidant/anti-inflammatory mechanisms such as NRF2 and PPARγ pathways, respectively. Paliperidone administration also stimulated the alternative polarization of microglia to the M2 anti-inflammatory profile. In addition, paliperidone treatment improved spatial working memory deficits of this SZ-like animal model. In conclusion, chronic administration of paliperidone to young-adult mice prenatally exposed to maternal immune (MIA) challenge elicits a general preventive anti-inflammatory/antioxidant effect at both intracellular and cellular polarization (M1/M2) level in FC, as well as ameliorates specific cognitive deficits.Item Paliperidone Prevents Brain Toll-Like Receptor 4 Pathway Activation and Neuroinflammation in Rat Models of Acute and Chronic Restraint Stress(International Journal of Neuropsychopharmacology, 2015) Mac-Dowell Mata, Karina Soledad; Caso Fernández, Javier Rubén; Martín Hernández, D.; Muñoz Madrigal, José Luis; Leza Cerro, Juan Carlos; García Bueno, BorjaBackground: Alterations in the innate immune/inflammatory system have been proposed to underlie the pathophysiology of psychotic disease, but the mechanisms implicated remain elusive. The main agents of the innate immunity are the family of toll-like receptors (TLRs), which detect circulating pathogen-associated molecular patterns and endogenous damage-associated molecular patterns (DAMPS). Current antipsychotics are able to modulate pro- and anti-inflammatory pathways, but their actions on TLRs remain unexplored. Methods: This study was conducted to elucidate the effects of paliperidone (1mg/Kg i.p.) on acute (6 hours) and chronic (6 hours/day during 21 consecutive days) restraint stress-induced TLR-4 pathway activation and neuroinflammation, and the possible mechanism(s) related (bacterial translocation and/or DAMPs activation). The expression of the elements of a TLR-4-dependent proinflammatory pathway was analyzed at the mRNA and protein levels in prefrontal cortex samples. Results: Paliperidone pre-treatment prevented TLR-4 activation and neuroinflammation in the prefrontal cortices of stressed rats. Regarding the possible mechanisms implicated, paliperidone regulated stress-induced increased intestinal inflammation and plasma lipopolysaccharide levels. In addition, paliperidone also prevented the activation of the endogenous activators of TLR-4 HSP70 and HGMB-1. Conclusions: Our results showed a regulatory role of paliperidone on brain TLR-4, which could explain the therapeutic benefits of its use for the treatment of psychotic diseases beyond its effects on dopamine and serotonin neurotransmission. The study of the mechanisms implicated suggests that gut-increased permeability, inflammation, and bacterial translocation of Gram-negative microflora and HSP70 and HGMB1 expression could be potential adjuvant therapeutic targets for the treatment of psychotic and other stress-related psychiatric pathologies.Item Risperidone administered during adolescence induced metabolic, anatomical and inflammatory/oxidative changes in adult brain: A PET and MRI study in the maternal immune stimulation animal model(European Neuropsychopharmacology, 2019) Casquero-Veiga, Marta; García-García, David; Pérez-Caballero, Laura; Torres-Sánchez, Sonia; Berrocoso, Esther; Desco, Manuel; Soto-Montenegro, María Luisa; Mac-Dowell Mata, Karina Soledad; Fraguas Herráez, David; Leza Cerro, Juan Carlos; Arango López, CelsoInflammation and oxidative stress (IOS) are considered key pathophysiological elements in the development of mental disorders. Recent studies demonstrated that the antipsychotic risperidone elicits an antiinflammatory effect in the brain. We administered risperidone for 2-weeks at adolescence to assess its role in preventing brain-related IOS changes in the maternal immune stimulation (MIS) model at adulthood. We also investigated the development of volumetric and neurotrophic abnormalities in areas related to the HPA-axis. Poly I:C (MIS) or saline (Sal) were injected into pregnant Wistar rats on GD15. Male offspring received risperidone or vehicle daily from PND35-PND49. We studied 4 groups (8-15 animals/group): Sal-vehicle, MIS-vehicle, Sal-risperidone and MIS-risperidone. [18F]FDG-PET and MRI studies were performed at adulthood and analyzed using SPM12 software. IOS and neurotrophic markers were measured using WB and ELISA assays in brain tissue. Risperidone elicited a protective function of schizophrenia-related IOS deficits. In particular, risperidone elicited the following effects: reduced volume in the ventricles and the pituitary gland; reduced glucose metabolism in the cerebellum, periaqueductal gray matter, and parietal cortex; higher FDG uptake in the cingulate cortex, hippocampus, thalamus, and brainstem; reduced NFκB activity and iNOS expression; and increased enzymatic activity of CAT and SOD in some brain areas. Our study suggests that some schizophrenia-related IOS changes can be prevented in the MIS model. It also stresses the need to search for novel strategies based on anti-inflammatory compounds in risk populations at early stages in order to alter the course of the disease.Item Gut microbiota, innate immune pathways, and inflammatory control mechanisms in patients with major depressive disorder(Translational Psychiatry, 2021) González-Pinto, Ana; García, Saínza; Diego-Adeliño, Javier de; Carceller-Sindreu, Mar; Sarramea, Fernando; Caballero-Villarraso, Javier; Gracia-García, Patricia; De la Cámara, Concepción; Rodríguez, Juan M.; Caso Fernández, Javier Rubén; Mac-Dowell Mata, Karina Soledad; Leza Cerro, Juan Carlos; Gómez-Lus Centelles, María Luisa; Agüera Ortiz, Luis Fernando; Alba Rubio, ClaudioAlthough alterations in the gut microbiota have been linked to the pathophysiology of major depressive disorder (MDD), including through effects on the immune response, our understanding is deficient about the straight connection patterns among microbiota and MDD in patients. Male and female MDD patients were recruited: 46 patients with a current active MDD (a-MDD) and 22 in remission or with only mild symptoms (r-MDD). Forty-five healthy controls (HC) were also recruited. Psychopathological states were assessed, and fecal and blood samples were collected. Results indicated that the inducible nitric oxide synthase expression was higher in MDD patients compared with HC and the oxidative stress levels were greater in the a-MDD group. Furthermore, the lipopolysaccharide (an indirect marker of bacterial translocation) was higher in a-MDD patients compared with the other groups. Fecal samples did not cluster according to the presence or the absence of MDD. There were bacterial genera whose relative abundance was altered in MDD:Bilophila(2-fold) andAlistipes(1.5-fold) were higher, whileAnaerostipes(1.5-fold) andDialister(15-fold) were lower in MDD patients compared with HC. Patients with a-MDD presented higher relative abundance ofAlistipesandAnaerostipes(1.5-fold) and a complete depletion ofDialistercompared with HC. Patients with r-MDD presented higher abundance ofBilophila(2.5-fold) compared with HC. Thus, the abundance of bacterial genera and some immune pathways, both with potential implications in the pathophysiology of depression, appear to be altered in MDD, with the most noticeable changes occurring in patients with the worse clinical condition, the a-MDD group.Item Periodontal diseases and depression: A pre‐clinical in vivo study(Journal of Clinical Periodontology, 2021) Martínez, María; Martín‐Hernández, David; Virto Ruiz, Leire; Mac-Dowell Mata, Karina Soledad; Leza Cerro, Juan Carlos; García Bueno, Borja; Figuero Ruiz, Elena; Ambrosio Elejalde, Nagore; Herrera González, David; Montero Solís, Eduardo; González Bris, Álvaro; Marín Cuenda, María José; Sanz Martín, MarianoAim: To analyse, through a pre-clinical in vivo model, the possible mechanisms linking depression and periodontitis at behavioural, microbiological and molecular levels. Materials and methods: Periodontitis (P) was induced in Wistar:Han rats (oral gavages with Porphyromonas gingivalis and Fusobacterium nucleatum) during 12 weeks, followed by a 3-week period of Chronic Mild Stress (CMS) induction. Four groups (n = 12 rats/group) were obtained: periodontitis and CMS (P+CMS+); periodontitis without CMS; CMS without periodontitis; and control. Periodontal clinical variables, alveolar bone levels (ABL), depressive-like behaviour, microbial counts and expression of inflammatory mediators in plasma and brain frontal cortex (FC), were measured. ANOVA tests were applied. Results: The highest values for ABL occurred in the P+CMS+ group, which also presented the highest expression of pro-inflammatory mediators (TNF-α, IL-1β and NF-kB) in frontal cortex, related to the lipoprotein APOA1-mediated transport of bacterial lipopolysaccharide to the brain and the detection of F. nucleatum in the brain parenchyma. A dysregulation of the hypothalamic-pituitary-adrenal stress axis, reflected by the increase in plasma corticosterone and glucocorticoid receptor levels in FC, was also found in this group. Conclusions: Neuroinflammation induced by F. nucleatum (through a leaky mouth) might act as the linking mechanism between periodontal diseases and depression.Item Peripheral Endocannabinoid System Dysregulation in First-Episode Psychosis(Neuropsychopharmacology, 2013) Bioque, Miquel; García Bueno, Borja; Mac-Dowell Mata, Karina Soledad; Meseguer, Ana; Saiz, Pilar ; Parellada Redondo, María José; Gonzalez-Pinto, Ana; Rodríguez Jiménez, Roberto; Lobo, Antonio; Leza Cerro, Juan Carlos; Bernardo, MiguelSeveral hypotheses involving alterations of the immune system have been proposed among etiological explanations for psychotic disorders. The endocannabinoid system (ECS) has a homeostatic role as an endogenous neuroprotective and anti-inflammatory system. Alterations of this system have been associated with psychosis. Cannabis use is a robust risk factor for these disorders that could alter the ECS signalling. In this study, 95 patients with a first episode of psychosis (FEP) and 90 healthy controls were recruited. Protein expression of cannabinoid receptor 2 (CB2), the protein levels of the main endocannabinoid synthesizing enzymes N-acyl phosphatidylethanolamine phospholipase (NAPE) and diacylglycerol lipase (DAGL), and of degradation enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) were determined by western blot analysis in peripheral blood mononuclear cells (PBMCs). Patients with a FEP showed a decreased expression of CB2 and of both endocannabinoids synthesizing enzymes (NAPE and DAGL) in comparison to healthy controls. After controlling for age, gender, body mass index, and cannabis use, NAPE and DAGL expression remained significantly decreased, whereas FAAH and MAGL expression were increased. On the other hand, FEP subjects with history of severe cannabis use showed a larger ECS dysregulation compared with healthy controls. These results indicate an ECS dysregulation in PBMC of FEP patients. The alteration of the ECS presented at the initial phases of psychosis could be contributing to the pathophysiology of the disease and constitutes a possible biomarker of psychotic disorders and an interesting pharmacological target to take into account for therapeutic purposes.Item Risperidone normalizes increased inflammatory parameters and restores anti-inflammatory pathways in a model of neuroinflammation(International Journal of Neuropsychopharmacology, 2013) Mac-Dowell Mata, Karina Soledad; García Bueno, Borja; Muñoz Madrigal, José Luis; Parellada, Mara; Arango López, Celso; Micó, Juan A.; Leza Cerro, Juan Carlos; Parellada Redondo, María JoséInflammation, caused by both external and endogenous factors, has been implicated as a main pathophysiological feature of chronic mental illnesses, including schizophrenia. An increase in pro-inflammatory cytokines has been described both in experimental models and in schizophrenia patients. However, not much is known about the effects that antipsychotic drugs have on intra- and intercellular mechanisms controlling inflammation. The aim of the present study was to investigate the possible anti-inflammatory effect of a standard schizophrenia treatment not only at the level of soluble mediators, but also at intra- and intercellular inflammatory pathways. The present study was conducted in a model of mild neuroinflammation using a lipopolysaccharide (LPS) challenge that was not an endotoxaemic dose (0.5 mg/kg i.p.) in young adult rats. Main results: single doses of risperidone (0.3–3.0 mg/kg i.p.) prevented increased inflammatory parameters induced by LPS in brain cortex [expression of inflammatory cytokines, interleukin (IL)-1β and tumour necrosis factor (TNF)-α, activity of the inducible inflammatory enzymes nitric oxide synthase and cyclooxygenase, p38 mitogen-activated protein kinase (MAPK) and inflammatory nuclear transcription factor κB] and restored anti-inflammatory pathways decreased by LPS challenge (deoxyprostaglandins and peroxisome proliferator activated receptor γ). This is the first study demonstrating that risperidone elicits a preventive effect on the anti-inflammatory arm of the homeostatic mechanism controlling inflammation in a model of mild encephalitis in rats. Our findings suggest a possible protective effect of risperidone on brain cells.Item Pro-/Anti-inflammatory Dysregulation in Patients With First Episode of Psychosis: Toward an Integrative Inflammatory Hypothesis of Schizophrenia(Schizophrenia Bulletin, 2014) García Bueno, Borja; Mac-Dowell Mata, Karina Soledad; Rodríguez Jiménez, Roberto; Rubio Valladolid, Gabriel; Leza Cerro, Juan CarlosBackground: Schizophrenia is a chronic syndrome of unknown etiology, predominantly defined by signs of psychosis. The onset of the disorder occurs typically in late adolescence or early adulthood. Efforts to study pathophysiological mechanisms in early stages of the disease are crucial in order to prompt intervention. Methods: Case-control study of first-episode psychotic (FEP) patients and matched controls. We recruited 117 patients during the first year after their FEP according to the DSM-IV criteria and recruited 106 gender-, race-, and age-matched controls between September 2010 and June 2011. Results: Biochemical studies carried out in peripheral mononuclear blood cells (PMBC) and plasma evidence a significant increase in intracellular components of a main proinflammatory pathway, along with a significant decrease in the anti-inflammatory ones. Multivariate logistic regression analyses identified the expression of inducible isoforms of nitric oxide synthase and cyclooxygenase in PMBC and homocysteine plasma levels as the most reliable potential risk factors and the inhibitor of the inflammatory transcription factor NFκB, IκBα, and the anti-inflammatory prostaglandin 15d-PGJ2 as potential protection factors. Discussion: Taken as a whole, the results of this study indicate robust phenotypical differences at the cellular machinery level in PMBC of patients with FEP. Although more scientific evidence is needed, the determination of multiple components of pro- and anti-inflammatory cellular pathways including the activity of nuclear receptors has interesting potential as biological markers and potential risk/protective factors for FEP. Due to its soluble nature, a notable finding in this study is that the anti-inflammatory mediator 15d-PGJ2 might be used as plasmatic biomarker for first episodes of psychosis.Item Paliperidone Reversion of Maternal Immune Activation-Induced Changes on Brain Serotonin and Kynurenine Pathways(Frontiers in Pharmacology, 2021) Munarriz-Cuezva, Eva; Meana, J. Javier; Ortega, Jorge E.; Mac-Dowell Mata, Karina Soledad; Leza Cerro, Juan CarlosEmerging evidence indicates that early-life exposure to environmental factors may increase the risk for schizophrenia via inflammatory mechanisms. Inflammation can alter the metabolism of tryptophan through the oxidative kynurenine pathway to compounds with neurotoxic and neuroprotective activity and compromise serotonin (5-HT) synthesis. Here we investigate the role of serotonergic and kynurenine pathways in the maternal immune activation (MIA) animal model of schizophrenia. The potential reversion exerted by long-term antipsychotic treatment was also evaluated. MIA was induced by prenatal administration of polyinosinic:polycytidylic acid (poly (I:C)) in mice. Expression of different proteins and the content of different metabolites involved in the function of serotonergic and kynurenine pathways was assessed by RT-PCR, immunoblot and ELISA analyses in frontal cortex of the offspring after puberty. MIA decreased tissue 5-HT content and promoted changes in the expression of serotonin transporter, 5-HT2A and 5-HT2C receptors. Expression of indoleamine 2,3-dioxygenase 2 (IDO2) and kynurenine 3-monooxygenase (KMO) was increased by poly (I:C) whereas kynurenine aminotransferase II and its metabolite kynurenic acid were not altered. Long-term paliperidone was able to counteract MIA-induced changes in 5-HT and KMO, and to increase tryptophan availability and tryptophan hydroxylase-2 expression in poly (I:C) mice but not in controls. MIA-induced increase of the cytotoxic risk ratio of kynurenine metabolites (quinolinic/kynurenic acid) was also reversed by paliperidone. MIA induces specific long-term brain effects on serotonergic activity. Such effects seem to be related with alternative activation of the kynurenine metabolic pathway towards a cytotoxic status. Atypical antipsychotic paliperodine partially remediates abnormalities observed after MIA.